Discodermolide, more specifically referred to as (+)-discodermolide, is a microtubule-stabilizing drug which is found naturally in the Caribbean sponge Discodermia dissoluta. Discodermolide has attracted widespread attention because of its known potent inhibition of tumor cell growth. The structure of discodermolide is shown below:

As evidenced by the structure above, discodermolide is a structurally complex molecule. Contributing to its complexity are thirteen chiral centers, grouped as a stereotetrad (four contiguous chiral centers, C-2 to C-5)), an isolated chiral center (C-7), a stereotriad (three contiguous chiral centers (C-10 to C-12), and a stereopentad (five contiguous chiral centers, C-16 to C-20), and four olefinic bonds, three of which have specific geometry. The C-10 to C-12 stereotriad has syn, anti relative stereochemistry. This stereotriad (syn, anti) is also found within the stereotetrad and within the stereopentad.
The isolation of discodermolide from natural sources has not resulted in commercially meaningful quantities of the drug. Accordingly, there remains a continuing effort to find an efficient synthesis of discodermolide.
Because of the structural complexity of discodermolide, its synthesis has proven to be a formidable task. The synthesis of multigram quantities of discodermolide reported by Novartis in March 2004 required more than 20 steps in the longest linear sequence (more than 30 steps in total) and twenty months of work. See M. Freemantle, “Scaled-Up Synthesis of Discodermolide,” Chemical & Engineering News, Mar. 1, 2004, pp. 33-35.
The Novartis synthesis as reported, like other published total syntheses, was based on the elaboration of the well-known chiral fungal product, methyl (R)-2-methyl-3-hydroxypropionate (the “Roche ester”), as the source of chirality for all three key intermediates.

Recently, syntheses of key intermediates in which the source of chirality was a chiral auxiliary were reported. See Dias, Luiz C.; Bau, Rosana Z.; de Sousa, Marcio A.; Zukerman-Schpector, J. “High 1,5-Anti Stereoinduction in Boron-Mediated Aldol Reactions of Methyl Ketones” Organic Letters (2002), 4(24), 4325-4327 and Day, Billy W.; Kangani, Cyrous O.; Avor, Kwasi S. “Convenient syntheses of (2R,3S,4R)-3-(tert-butyldimethylsilanyloxy)-2,4-dimethyl-5-oxopentanoic acid methoxymethylamide from methacrolein. Preparation of C1-C7 and C17-C24 fragments of (+)-discodermolide.” Tetrahedron: Asymmetry (2002), 13(11), 1161-1165. This approach was incorporated in the Novartis scale-up studies; see Loiseleur, Olivier; Koch, Guido; Wagner, Trixie. “A Practical Building Block for the Synthesis of Discodermolide.” Organic Process Research & Development (2004), 8(4), 597-602 Also, recently, Myles and coworkers at Kosan prepared Smith's key intermediate, the common precursor “CP” by chemical modification of a fermentation product from a genetically engineered Streptomyces; see Burlingame, Mark A.; Mendoza, Esteban; Ashley, Gary W.; Myles, David C. “Synthesis of discodermolide intermediates from engineered polyketides” Tetrahedron Letters (2006), 47(7), 1209-1211.
There are other biologically active compounds which share some of the structural features of discodermolide. For example, the calyculins, natural products isolated from the marine sponge Discodermia calyx are inhibitors of serine-threonine phosphatase. Calyculins A and B are shown below. The encircled part of the structure shows a stereotetrad, that contains an anti, anti stereotriad at C-10 to C-12.

Likewise, the macrolide antitumor agent dictyostatin contains two syn, anti stereotriads, encircled in the picture, one of which is part of a stereotetrad.

Accordingly, there is a clear need for more efficient ways to produce polypropionate antibiotics in which there are stereotriad regions. Such improved syntheses can be realized by, for example, providing new chemical intermediates. Particularly beneficial for this purpose are new intermediates which conveniently provide the anti, syn stereotriad that is contained, for example, in the C8 to C14 portion of discodermolide. Also particularly beneficial are schemes that rely on asymmetric catalysis, rather than on expensive chiral starting materials such as the Roche ester or on chiral auxiliaries for the introduction of chirality.